This project tests the effects of maternal perinatal diet on skeletal acquisition. Perinatal developmental programming, triggered by perinatal caloric restriction or high fat diet, is a known risk factor for adult neuroendocrine, immune, reproductive, and metabolic disease, including obesity, atherosclerosis, and type II diabetes. However, little is known about how early life nutrition impacts skeletal development. The general hypothesis is that perinatal caloric restriction (CR) or high fat (HF) diet will initiate developmental programming that decreases postnatal bone growth and acquisition of bone mineral density. To test whether perinatal energetic status affects bone growth, mice exposed to maternal CR or HF diet during gestation/lactation will be compared to postnatally exposed mice. Previous studies have shown negative effects of CR and HF diets on bone in adult rodents, but did not test for effects on juvenile skeletal acquisition. Our specific aims include determining whether caloric availability (ad lib vs. restricted) and macronutrient source (high fat vs. high carbohydrate) during skeletal growth and/or maternal diet during pregnancy and lactation affect bone mass, microarchitecture and strength. We will also test whether prenatal diet affects the skeletal response to postnatal diet. The hypothesized mechanism for these bone-environment interactions involves signaling of energetic status by leptin, a fat-derived signal of energetic status, via ss-adrenergic receptors in bone. Thus our experiments will compare skeletal and hormonal response to prenatal and postnatal energy availability in normal mice and ss-adrenergic receptor2 knockout (ss2-AR KO) mice. By separating the effects of direct leptin action on bone from the effects of central leptin signaling in osteoblasts (absent in ss2-AR KO mice), we will generate unique data on the effects of central vs. peripheral leptin signaling on trabecular and cortical bone. PUBLIC HEALTH RELEVANCE: This project has several applications to human health. Osteoporosis and obesity are increasing markedly in society, and understanding how interactions between prenatal and postnatal nutrition affect the skeleton may help to identify mechanisms underlying attainment of bone mass and strength during growth.